ADC Histogram Analysis of Pediatric Low-Grade Glioma Treated with Selumetinib: A Report from the Pediatric Brain Tumor Consortium.

BACKGROUND AND PURPOSE: Selumetinib is a promising MAP (mitogen-activated protein) kinase (MEK) 1/2 inhibitor treatment for pediatric low-grade gliomas. We hypothesized that MR imaging-derived ADC histogram metrics would be associated with survival and response to treatment with selumetinib. MATERIALS AND METHODS: Children with recurrent, refractory, or progressive pediatric low-grade gliomas who had World Health Organization grade I pilocytic astrocytoma with KIAA1549-BRAF fusion or the BRAF V600E mutation (stratum 1), neurofibromatosis type 1-associated pediatric low-grade gliomas (stratum 3), or sporadic non-neurofibromatosis type 1 optic pathway and hypothalamic glioma (OPHG) (stratum 4) were treated with selumetinib for up to 2 years. Quantitative ADC histogram metrics were analyzed for total and enhancing tumor volumes at baseline and during treatment. RESULTS: Each stratum comprised 25 patients. Stratum 1 responders showed lower values of SD of baseline ADC_total as well as a larger decrease with time on treatment in ADC_total mean, mode, and median compared with nonresponders. Stratum 3 responders showed a greater longitudinal decrease in ADC_total. In stratum 4, higher baseline ADC_total skewness and kurtosis were associated with shorter progression-free survival. When all 3 strata were combined, responders showed a greater decrease with time in ADC_total mode and median. Compared with sporadic OPHG, neurofibromatosis type 1-associated OPHG had lower values of ADC_total mean, mode, and median as well as ADC_enhancement mean and median and higher values of ADC_total skewness and kurtosis at baseline. The longitudinal decrease in ADC_total median during treatment was significantly greater in sporadic OPHG compared with neurofibromatosis type 1-associated OPHG. CONCLUSIONS: ADC histogram metrics are associated with progression-free survival and response to treatment with selumetinib in pediatric low-grade gliomas.

Effects of Tissue Temperature and Injury on ADC during Therapeutic Hypothermia in Newborn Hypoxic-Ischemic Encephalopathy.

BACKGROUND AND PURPOSE: ADC changes are useful in detecting ischemic brain injury, but mechanisms other than tissue pathology may affect the kinetic movement and diffusion of water molecules. We aimed to determine the effects of brain temperature on the corresponding ADC in infants undergoing therapeutic hypothermia. MATERIALS AND METHODS: Brain temperature and ADC values in the basal ganglia, thalamus, cortical GM, and WM were analyzed during and after therapeutic hypothermia. The study cohort was categorized as having no-injury or injury. Among infants without injury, the correlation between ADC values and temperature was analyzed using the Pearson correlation. Intrasubject comparison of ADC changes during and after therapeutic hypothermia were analyzed, excluding patients who had an MR image interval of >5 days to minimize the effects of injury evolution. RESULTS: Thirty-nine infants with hypoxic-ischemic encephalopathy were enrolled (23 no-injury; 16 injury). The median ADC was significantly lower during therapeutic hypothermia (837; interquartile range, 771-928, versus 906; interquartile range, 844-1032 ×10-6mm2/s; P < .001). There was no difference in the ADC between the no-injury and injury groups during therapeutic hypothermia (823; interquartile range, 782-868, versus 842; interquartile range, 770-1008 ×10-6mm2/s; P = .4). In the no-injury group, in which ADC is presumed least affected by the evolution of injury, the median ADC was significantly lower during therapeutic hypothermia (826; interquartile range, 771-866, versus 897; interquartile range, 846-936 ×10-6mm2/s; P < .001). There was a moderate correlation between temperature and ADC in the no-injury group (during therapeutic hypothermia: Spearman ρ, 0.48; P < .001; after therapeutic hypothermia: ρ, 0.4; P < .001). CONCLUSIONS: Aside from brain injury, reduced tissue temperature may also contribute to diffusion restriction on MR imaging in infants undergoing therapeutic hypothermia.

Diffusion Characteristics of Pediatric Diffuse Midline Gliomas with Histone H3-K27M Mutation Using Apparent Diffusion Coefficient Histogram Analysis.

BACKGROUND AND PURPOSE: Diffuse midline gliomas with histone H3 K27M mutation are biologically aggressive tumors with poor prognosis defined as a new diagnostic entity in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. There are no qualitative imaging differences (enhancement, border, or central necrosis) between histone H3 wildtype and H3 K27M-mutant diffuse midline gliomas. Herein, we evaluated the utility of diffusion-weighted imaging to distinguish H3 K27M-mutant from histone H3 wildtype diffuse midline gliomas. MATERIALS AND METHODS: We identified 31 pediatric patients (younger than 21 years of age) with diffuse gliomas centered in midline structures that had undergone assessment for histone H3 K27M mutation. We measured ADC within these tumors using a voxel-based 3D whole-tumor measurement method. RESULTS: Our cohort included 18 infratentorial and 13 supratentorial diffuse gliomas centered in midline structures. Twenty-three (74%) tumors carried H3-K27M mutations. There was no difference in ADC histogram parameters (mean, median, minimum, maximum, percentiles) between mutant and wild-type tumors. Subgroup analysis based on tumor location also did not identify a difference in histogram descriptive statistics. Patients who survived <1 year after diagnosis had lower median ADC (1.10 × 10-3mm2/s; 95% CI, 0.90-1.30) compared with patients who survived >1 year (1.46 × 10-3mm2/s; 95% CI, 1.19-1.67; P < .06). Average ADC values for diffuse midline gliomas were 1.28 × 10-3mm2/s (95% CI, 1.21-1.34) and 0.86 × 10-3mm2/s (95% CI, 0.69-1.01) for hemispheric glioblastomas with P < .05. CONCLUSIONS: Although no statistically significant difference in diffusion characteristics was found between H3-K27M mutant and H3 wildtype diffuse midline gliomas, lower diffusivity corresponds to a lower survival rate at 1 year after diagnosis. These findings can have an impact on the anticipated clinical course for this patient population and offer providers and families guidance on clinical outcomes.

Pediatric Atypical Teratoid/Rhabdoid Tumors of the Brain: Identification of Metabolic Subgroups Using In Vivo 1H-MR Spectroscopy.

BACKGROUND AND PURPOSE: Atypical teratoid/rhabdoid tumors are rare, aggressive central nervous system tumors that are predominantly encountered in very young children. Our aim was to determine whether in vivo metabolic profiles correlate with molecular features of central nervous system pediatric atypical teratoid/rhabdoid tumors. MATERIALS AND METHODS: Twenty confirmed patients with atypical teratoid/rhabdoid tumors who underwent MR spectroscopy were included in this study. In vivo metabolite levels of atypical teratoid/rhabdoid tumors were compared with molecular subtypes assessed by achaete-scute homolog 1 expression. Additionally, brain-specific creatine kinase levels were determined in tissue samples. RESULTS: In vivo creatine concentrations were higher in tumors that demonstrated achaete-scute homolog 1 expression compared with those without achaete-scute homolog 1 expression (3.42 ± 1.1 versus 1.8 ± 0.8 IU, P < .01). Additionally, levels of myo-inositol (mI) (9.0 ± 1.5 versus 4.7 ± 3.6 IU, P < .05) were significantly different, whereas lipids approached significance (44 ± 20 versus 80 ± 30 IU, P = .07) in these 2 cohorts. Higher brain-specific creatine kinase levels were observed in the cohort with achaete-scute homolog 1 expression (P < .05). Pearson correlation analysis showed a significant positive correlation of brain-specific creatine kinase with absolute creatine (P < .05) and myo-inositol (P < .05) concentrations. CONCLUSIONS: In vivo MR spectroscopy may predict key molecular features of atypical teratoid/rhabdoid tumors at initial diagnosis, leading to timely patient risk stratification and accelerating the development of targeted therapies.

Use of electrical vestibular stimulation to alter genioglossal muscle activity in awake cats.

Prior work has shown that the vestibular system contributes to regulating activity of upper airway muscles including the tongue protruder muscle genioglossus. The goal of the present experiments was to determine whether electrical vestibular stimulation could potentially be used to alter genioglossal activity in awake animals. Six adult cats were instrumented for recording of EMG activity from genioglossus, abdominal musculature, and triceps. In addition, a silver ball electrode was implanted on the round window for stimulation of vestibular afferents. Subsequently, stimulation and recordings were conducted while animals were awake. In all cases, stimulation using single shocks or trains of pulses > 100 microA in intensity produced responses in all muscles, including genioglossus. The latency of the genioglossal response was approximately 12 msec, and delivering continuous current trains to the labyrinth chronically elevated the muscle's activity. Although a number of muscles were affected by the stimulus, animals experienced no obvious distress or balance disturbances. Vestibular stimulation remained effective in producing genioglossal responses until experiments were discontinued 1-2 months following onset. These data suggest that electrical vestibular stimulation could potentially be used therapeutically to alter upper airway muscle activity.